Surgery, radiotherapy and chemotherapy are standard modalities used by oncologists for treatment of most cancers, but many malignancies either at presentation of when they recur, cannot be successfully treated with such methods. Renal cell carcinoma falls into this category, and in addition, presents the treating physician with several perplexing and interesting problems. These include large primary tumors, frequent vascular invasion without metastases, solitary metastases, and uncommon but well documented spontaneous regressions. In addition, recent observations indicate this is one of several tumors (including malignant melanoma) that respond to various biologic response modifiers. With the significant advances in our understanding of the immune system, there is expectation that immunologic approaches to treatment of cancers, such as renal cell carcinoma, will provide new and effective methods of disease control. Additionally, the recognition that renal cell carcinoma may be associated with an abnormality of chromosome 3, and DNA sequence deletions are present at the 3p region in this tumor, have raised the possibility a gene located in this region may be involved in the pathogenesis of renal cancer. The program now proposes to study the biology of RCC at the clinical, immunologic, and molecular levels. Clinical trials utilizing various cytokine combinations are planned, and will be accompanied by investigations of immunologic changes occurring as a result of this therapy. The actions of cytokine combinations (IL-2/IL-4, IL-2/IFNalpha) will be studied and detailed investigations of mechanisms and synergistic activities at the molecular level will be undertaken. Finally, the tumor itself will be studied. The molecular genetics of RCC will be investigated, and will include identification of putative suppressor gene(s) and the actions of their products. This dual approach investigating cytokine therapy and the molecular characteristics of RCC are complementary. The unifying theme of this program is the investigation of the biologic features of human renal cell carcinoma, with the ultimate goals being improvement in therapy, and an understanding of tumor development. The characteristics of renal cell carcinoma, and our previous laboratory and clinical studies have influenced the development of the present program project.